Abstract

Cisplatin and derivatives are commonly used as chemotherapeutic agents. Although the cytotoxic action of cisplatin on cancer cells is very efficient, clinical oncologists need to deal with two major difficulties: (i) the onset of resistance to the drug, and (ii) the cytotoxic effect in patients. Here we use Caenorhabditis elegans to investigate factors influencing the response to cisplatin in multicellular organisms. In this hermaphroditic model organism, we observed that sperm failure is a major cause in cisplatin-induced infertility. RNA-seq data indicate that cisplatin triggers a systemic stress response in which DAF-16/FOXO and SKN-1/Nrf2, two conserved transcription factors, are key regulators. We determined that inhibition of the DNA-damage induced apoptotic pathway does not confer cisplatin protection to the animal. However, mutants for the pro-apoptotic BH3-only gene ced-13 are sensitive to cisplatin, suggesting a protective role of the intrinsic apoptotic pathway. Finally, we demonstrate that our system can also be used to identify mutations providing resistance to cisplatin and therefore potential biomarkers of innate cisplatin-refractory patients. We show that mutants for the redox regulator trxr-1, ortholog of the mammalian Thioredoxin-Reductase-1 TrxR1, display cisplatin resistance. By CRISPR/Cas9 we determined that such resistance relies on the presence of the single selenocysteine residue in TRXR-1.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

Trichur R. Raju and colleagues explore how the pathological changes of the skeletal muscle can significantly damage motor neurons, leading to progressive neurodegeneration in amyotrophic lateral sclerosis.

The chronic pain experienced by a number of patients with diabetes has widely been assumed to originate from damage to blood vessels or to local tissue surrounding neurons caused by high blood-sugar levels. However, a new study reports that in fruit flies, this pain hypersensitivity results instead from disrupted insulin signalling in pain sensory neurons.

Currently used animal models of critical-sized bone defects and the regenerative bone tissue engineering strategies used in these models are reviewed by Jacqui Anne McGovern, Michelle Griffin and Dietmar Werner Hutmacher, as well as the application of bone tissue engineering for the advancement of cancer xenograft models.

We are currently seeking proposals for four Workshops to be held in 2020. Do you have an idea for a Workshop? Please let us know and you could be one of our 2020 Workshop organisers. You focus on the science, we focus on the logistics. We are particularly keen to receive proposals from postdocs. Deadline date for applications is 25 May 2018.

Elizabeth Rhea, a postdoctoral fellow at the University of Washington, USA, used a Travelling Fellowship from DMM to travel to Monash University in Melbourne, Australia. There, Elizabeth worked on developing a method to use the buccal mucosa as a model for screening enhancers of intranasal insulin delivery. Read more on her story here.

Where could your research take you? Join Elizabeth and apply for the next round of Travelling Fellowships from DMM by 25 May 2018.

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preLights is the new preprint highlights service run by the biological community and supported by The Company of Biologists.

Meet the preLighters! In the latest interview with our preLights community, the preLights team caught up with James Gagnon, Assistant Professor at the University of Utah, to talk about his research, how science can be made more open, his enthusiasm for the preLights project and the fun sides of being a junior PI.